THE ROLE OF 1,25 DIHYDOXYVITAMIN D DURING FETAL LIFE

许多早产儿在出生后的最初 24 小时内会出现低钙血症。 生活。 其中，百分之二十可能有后续的骨骼 demineralization (osteopenia, rickets, long bone fractures). 的 underlying mechanisms are unknown but may involve abnormal vitamin D 新陈代谢。 本提案旨在帮助明确 the hormonal form of vitamin D, namely, 1,25 dihydroxyvitamin D (1,25(OH)2D) in the mineral economy of the fetus during intrauterine life. The following specific questions will be addressed: 1) What are the relative contributions of the fetal kidney and the placenta to fetal circulating 1,25(OH)2D concentrations during intrauterine life? 2) 是 normal fetal circulating 1,25(OH)2D concentrations necessary for normal 宫内矿物质代谢？ 3）胎盘和胎儿的骨头吗 responsive target organs for the action of 1,25(OH)2D during fetal life? In phase I of our study, singleton sheep fetuses will be instrumented at 110 days of gestation (term 145) to determine the 1,25(OH)2D synthetic 胎儿胎盘单位的容量。 这将通过测量来完成 the fetal Production and Metabolic Clearance Rates of 1,25(OH)2D and by measurement of the in vivo placental synthesis rate using an in vivo 胎盘灌注技术。 与妊娠相关的正常变化 血清矿物质和钙调节激素也将被评估 longitudinally from 110 days to 138 days of gestation when normal placental 将确定矿物质转移和胎儿矿物质利用率。 在我们研究的第二阶段，我们将使用双侧肾切除的胎儿 determine the impact of loss of fetal renal 1,25(OH)2D synthetic capacity on fetal serum 1,25(OH)2D and mineral concentrations, placental mineral 转移和胎儿矿物质利用率。 根据我们之前的 研究表明，胎儿肾切除术会导致胎儿低钙血症， 高磷血症和胎儿血清 1,25(OH)2D 浓度降低。 我们 假设这些变化是由 1,25(OH)2D 介导的减少引起的 胎盘矿物质转移和正常骨矿化的破坏 通过外源性 1,25(OH)2D 疗法可以在很大程度上得到纠正。 这些综合研究将为功能性提供有价值的见解。 1,25(OH)2D 在胎儿生命中的作用，因为它与以下病因有关 早产儿低钙血症和骨脱矿。

Many premature infants develop hypocalcemia during the first 24 hours of life. Of these, twenty percent may have subsequent skeletal demineralization (osteopenia, rickets, long bone fractures). The underlying mechanisms are unknown but may involve abnormal vitamin D metabolism. The present proposal is designed to help clarify the role of the hormonal form of vitamin D, namely, 1,25 dihydroxyvitamin D (1,25(OH)2D) in the mineral economy of the fetus during intrauterine life. The following specific questions will be addressed: 1) What are the relative contributions of the fetal kidney and the placenta to fetal circulating 1,25(OH)2D concentrations during intrauterine life? 2) Are normal fetal circulating 1,25(OH)2D concentrations necessary for normal intrauterine mineral metabolism? 3) Are the placenta and fetal bone responsive target organs for the action of 1,25(OH)2D during fetal life? In phase I of our study, singleton sheep fetuses will be instrumented at 110 days of gestation (term 145) to determine the 1,25(OH)2D synthetic capacity of the fetal-placental unit. This will be done by measurement of the fetal Production and Metabolic Clearance Rates of 1,25(OH)2D and by measurement of the in vivo placental synthesis rate using an in vivo placental perfusion technique. Normal gestationally related changes in serum minerals and calcium regulating hormones will also be assessed longitudinally from 110 days to 138 days of gestation when normal placental mineral transfer and fetal mineral utilization rates will be determined. In phase II of our study, we will use bilaterally nephrectomized fetuses to determine the impact of loss of fetal renal 1,25(OH)2D synthetic capacity on fetal serum 1,25(OH)2D and mineral concentrations, placental mineral transfer and fetal mineral utilization rates. Based on our previous studies, fetal nephrectomy will result in fetal hypocalcemia, hyperphosphatemia and reduced fetal serum 1,25(OH)2D concentrations. We hypothesize that these changes result from reduced 1,25(OH)2D-mediated placental mineral transfer and disruption of normal bone mineralization and will be largely corrected by treatment with exogenous 1,25(OH)2D therapy. These combined studies will provide valuable insight into the functional role of 1,25(OH)2D during fetal life, as it relates to the etiology of hypocalcemia and bone demineralization in prematurity.